Hypoglycemia Among Type 2 Diabetics Fasting Ramadan Dr Hypoglycemia Among Type 2 Diabetics Fasting Ramadan Dr. Khaled Tayeb tayebkhaled@hotmail.com

To Fast during the month of Ramadan-Prayer and supplication to God-Discipline to be observed during the month-Rights of property to be respected (183) يَا أَيُّهَا الَّذِينَ آمَنُواْ كُتِبَ عَلَيْكُمُ الصِّيَامُ كَمَا كُتِبَ عَلَى الَّذِينَ مِن قَبْلِكُمْ لَعَلَّكُمْ تَتَّقُونَ (184) أَيَّامًا مَّعْدُودَاتٍ فَمَن كَانَ مِنكُم مَّرِيضًا أَوْ عَلَى سَفَرٍ فَعِدَّةٌ مِّنْ أَيَّامٍ أُخَرَ وَعَلَى الَّذِينَ يُطِيقُونَهُ فِدْيَةٌ طَعَامُ مِسْكِينٍ فَمَن تَطَوَّعَ خَيْرًا فَهُوَ خَيْرٌ لَّهُ وَأَن تَصُومُواْ خَيْرٌ لَّكُمْ إِن كُنتُمْ تَعْلَمُونَ (185) شَهْرُ رَمَضَانَ الَّذِيَ أُنزِلَ فِيهِ الْقُرْآنُ هُدًى لِّلنَّاسِ وَبَيِّنَاتٍ مِّنَ الْهُدَى وَالْفُرْقَانِ فَمَن شَهِدَ مِنكُمُ الشَّهْرَ فَلْيَصُمْهُ وَمَن كَانَ مَرِيضًا أَوْ عَلَى سَفَرٍ فَعِدَّةٌ مِّنْ أَيَّامٍ أُخَرَ يُرِيدُ اللّهُ بِكُمُ الْيُسْرَ وَلاَ يُرِيدُ بِكُمُ الْعُسْرَ وَلِتُكْمِلُواْ الْعِدَّةَ وَلِتُكَبِّرُواْ اللّهَ عَلَى مَا هَدَاكُمْ وَلَعَلَّكُمْ تَشْكُرُونَ

Recommendations for Management of Diabetes During Ramadan Diabetes Care Volume 33, Number 8, August 2010

Major risk associated with fasting in patients with diabetes Hypoglycemia Hyperglycemia Diabetic ketoacidosis Dehydration and thrombosis Recommendations for Diabetic Individuals during Ramadan, Diabetes Care , vol 33, num. 8, August2010

Hypoglycaemia 2 – 4% of mortality in patients with type 1 diabetes. Rates of hypoglycaemia are some several-fold lower in patients with type 2 compared with type 1 diabetes Rates being lower in patients with type 2 diabetes treated with oral agents. Recommendations for Diabetic Individuals during Ramadan, Diabetes Care , vol 33, num. 8, August2010

Categories of risks in patients with type 1 or type 2 diabetes who fast during Ramadan 1. Very high risk Severe hypoglycaemia within the last 3 months prior to Ramadan. A history of recurrent hypoglycaemia. Hypoglycaemia unawareness. Sustained poor glycemic control. Ketoacidosis within the last 3 months prior to Ramadan. Recommendations for Diabetic Individuals during Ramadan, Diabetes Care , vol 33, num. 8, August2010

Breaking the Fast All patients must always and immediately end their fast if: Hypoglycaemia (blood glucose of <60mg/dl). Blood glucose reaches <70 mg in the first few hours after the start of the fast, especially if insulin, sulfonylurea drugs, or neglitinide are taken at predawn. Blood glucose exceeds 300 mg with symptoms of hyperglycaemia. Recommendations for Diabetic Individuals during Ramadan, Diabetes Care , vol 33, num. 8, August2010

(4.7 fold) (7.5 fold)

Change in outcome measures during Ramadan in participants receiving both gliclazide and metformin1 Hypoglycaemia in study control group on Metfromin + Gliclazide Ramadan 2008 Int J Clin Pract 2009; 63: 1446–50 10 10 10

Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242 Hypoglycemia in Sulphonylurea-Treated Subjects with Type 2 Diabetes Undergoing Ramadan Fasting: A Five-Country Observational Study Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242 Objectives To determine the incidence of hypoglycemia during Ramadan in Muslim subjects with type 2 diabetes treated with a sulphonylurea. Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242 Subjects & Methods Eligible subjects Muslim patients with type 2 diabetes treated with Sulphonylureas( Glimiperide, Glyclazide , or Glibenclamide) With or without Metformin Age ≥ 18 years old Excluded subjects Patients with Type 1 diabetes Patients with Insulin treated type 2 diabetes Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242 Subjects & Methods Subjects were recruited from 5 countries. 300 subjects were selected per country. Diabetes Center in Holy Makkah and other centers from (UAE, India, Malaysia, and occupied Palestine ). Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242 Subjects & Methods Patients were given a daily dairy card to record .. any hypoglycemic symptoms and complications The time from the start of hypoglycemic symptoms and the last meal and medications Self monitor blood glucose Need for assistance to treat hypos. The fasting was broken or not. Cards to be filled daily regardless of symptoms Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242 Subjects & Methods The hypoglycemic events were further classified into.. - Symptomatic : (headache, sweating, tremors, palpitation, etc..) - Documented: symptomatic with BG ≤ 70 mg/dl. - Severe: requiring medical or non- medical assistance. Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Patients Characteristic in the Study Overall (N=1378) Glipizide (n=29) Glibenclamide (n=535) Gliclazide (n=386) Glimepiride (n=428) 729 (53 %) 12 (41 %) 263 (49 %) 225 (58 %) 229 (54 %) Gender M 53.8 ± 10.0 58.1± 9.8 55.5 ± 10.0 53.7 ± 9.2 51.4 ± 10.1 Age at baseline, yrs 46.6 ± 9.9 45.0 ± 18.5 29.4 ± 10.0 29.0 ± 5.3 28.4 ± 5.2 BMI, kg/m2 46.6± 9.9 47.5 ± 10.0 46.9 ± 8.9 45.3 ± 9.6 Age at diabetes diagnosis, yrs Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Sulponylurea use by country in the study Overall (N=1378) Glipizide (n=29) Glibenclamide (n=535) Gliclazide (n=386) Glimepiride (n=428) Country 396 (29%) 0 (0%) 107 (20%) 50 (13%) 239 (56%) India 247 (18%) 29 (100%) 170 (32%) 48 (11%) Occupied Palestine 355 (26%) 144 (27%) 182 (47%) 29 (7%) Malaysia 363 (26%) 114 (37%) 141 (37%) 108 (25%) Saudi Arabia 17 (1%) 13 (3%) 4 (1%) UAE Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242 Results The daily dairy card were returned by 1378 patients from total 1397 patients. Symptomatic hypoglycemia was 40% in occupied Palestine and 10% in Saudi Arabia Over all symptomatic hypoglycemic events were recorded in 271 subjects (19.7%) Headache represent 14.5%, sweating 10.2%, tremors 8.5% and palpitation 7%. Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Incidence of symptomatic hypoglycemia during Ramadan by countries N of Patients Countries 40% Occupied Palestine 24% Malaysia 18% United Arab Emirates 13% India 10% Saudi Arabia Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Incidence of hypoglycemia during Ramadan by type Percentage (%) Type of hypoglycemia 86 Symptomatic hypoglycemic events 3.6 Documented hypoglycemic events 3.7 Severe hypoglycemic events 6.7 Severe hypoglycemic events requiring medical assistance Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Incidence of hypoglycemia during Ramadan by type 86% 6.7% 3.6% 3.7% Symptomatic hypoglycemic events Documented hypoglycemic events Severe hypoglycemic events Severe hypoglycemic events requiring medical assistance Type of hypoglycemia

Incidence of hypoglycemia during Ramadan by types of drug Overall (N=1378) Glipizide (n=29) Glibenclamide (n=535) Gliclazide (n=386) Glimepiride (n=428) N of patients (%) 271 19.7% 8 (27.6%) 137 (25.6%) 54 (14 %) 72 (16.8%) Symptomatic hypoglycemic events 49 3.6% 0 (0.0%) 21 (3.9%) 11 (2.8%) 17 (4.0%) Documented hypoglycemic events 92 6.7% 2 (6.9%) 58 (10.8%) 10 (2.6%) 22 (5.1%) Severe hypoglycemic events 51 3.7% 36 (6.5%) 6 (1.6%) 10 (2.3%) Severe hypoglycemic events requiring medical assistance Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242 Results Symptomatic hypoglycemia events 1095 Documented hypoglycemic events were similar across all sulphonylurea groups 3.6%, . Events not requiring medical assistance 3.7% Events requiring assistance 6.7% . Subjects experienced a serious complication 1.2% . Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242 Discussion The incidence of severe hypoglycemia requiring medical or non medical assistance or hospitalization were less than other studies. In the EPIDAR study, 2% of patients hospitalized in comparison to 0.5% in this study. (Diabetes Care 2004; 2306-11) Health care resources utilization, was less in this study. The less severe hypoglycemia events or better education regarding the symptoms could explain this. Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242 The incidence of Hypoglycaemia in Muslim Type 2 Diabetics treated with Sitagliptin or a Sulphoylurea during Ramadan. Aim To compare the incidence of symptomatic hypoglycaemia with Sitagliptin or A Sulphonylurea during Ramadan. Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Patients and study design A prospective, open-label, randomised study. 6 countries, 43 clinical sites. 1243 patients of whom 1066 randomized to treatment. Muslim Type 2 diabetics willing to fast Ramadan. Age : > 18 Yrs. Treated with a sulphonylurea for at least 3 months before study with or without metformin and had HbA1c < 10%. Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242 Pre-Randomization Treatment Sulphonylurea ( n = 514 ) Sitagliptin ( n = 507 ) 181 (35%) 158 (31%) Glibenclamide 178 (35%) 189 (37%) Glimepiride 152 (30%) 159 (32%) Glicalazide 41 (8%) Monotherapy 471 (92%) 465 (92%) Dual ( SU + MET ), n (%) 4.0 Duration of SU Therapy* yrs 76 (15%) 81 (16%) Experienced hypoglycaemia in 3 M before Ramadan Data are expressed as frequency, n(%) or mean ± standard deviation unless otherwise indicated. *median Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242 Results 1066 patients randomised, 1021 enrolled in the study as they returned at least one complete diary. Incidence of symptomatic hypoglycaemic events - Sitagliptin group (5.1%) - Sulphonylurea group (11.9). Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242 Results Overall Egypt Palestien Jordan Lebanon Saudi Arabia UAE *n/N (%) Sitagliptin Sulphonylurea 5.1% 11.9% 0% 18.6% 10.3% 22.1% 6.7% 7.1% 9.9% 21.2% 0.5% 20.0% *no of patients experiencing event /N overall or in each country by treatment. (%) Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242 Results Sulphonylurea ( n = 514 ) n (%) of patients Experiencing event Sitagliptin ( n = 507 ) n ( %) of patients 84 ( 16.3% ) 35 ( 6.9% ) Symptomatic or asymptomatic hypoglycemic events Severe hypoglycemic events 3 ( 0.6% ) 1 ( 0.2% ) Hypoglycemic events requiring non-medical assistance Hypoglycemic events requiring medical assistance * Types of hypoglycemic event defined in Methods Current Medical Research & Opinion Vol. 27, No. 6, 2011, 1237-1242

Fear of hypoglycemia is a major concern for patients Male Female Severe hypoglycemia Male Female Mild hypoglycemia Male Female Kidney problems Pramming et al. evaluated the frequency of symptomatic hypoglycemic episodes in 411 randomly selected conventionally treated T1DM outpatients.1 Between two consecutive visits to the outpatient clinic, each patient filled in a questionnaire at home. The number of hypoglycemic episodes was then recorded prospectively in a diary for one week. From the questionnaires, the (retrospective) frequencies of mild and severe symptomatic hypoglycemia were 1.6 and 0.029 episodes/patient/week. From the diaries, the (prospective) frequencies of mild and severe hypoglycemic episodes were 1.8 and 0.027/patient/week. Symptomatic hypoglycemia was more frequent on working days than during weekends (1.8:1) and more frequent in the morning than during the afternoon, evening, and night (4.5:2.2:1.4:1). The study showed that during their diabetic life, 36% of the patients had experienced hypoglycemic coma and that severity of hypoglycemia was their biggest concern in managing their diabetes. This slide shows the relative degrees of fear towards different complications of diabetes, as reported by the study population using a visual analog scale. Reference Pramming S, Thorsteinsson B, Bendtson I et al. Symptomatic hypoglycemia in 411 type 1 diabetic patients. Diabet Med 1991;8:217–222. Blindness Male Female Very worried Not worried 1. Pramming S et al. Diabet Med 1991;8:217–222 32

Hypoglycaemic Events X4 increase

VECTOR: Aim and objectives Main aim To determine the incidence of hypoglycaemic events in 100 Muslim patients with T2D fasting during Ramadan, who are treated with dual therapy of metformin plus vildagliptin or metformin plus sulphonylurea (SU) Primary objectives the incidence of hypoglycaemic events defined as: Any reported symptoms by the patient and/or any blood glucose measurement of less than 3.9 mmol/L (also defined as mild or Grade 1 hypoglycaemia) The need for third party assistance (also defined as severe or Grade 2 hypoglycaemia); Secondary objectives the change in weight; the change in HbA1c levels; and the treatment adherence during Ramadan.

VECTOR: Results - Hypoglycaemic events (HE) Mean between-group difference in patients who experienced at least one HE was –41·7% (p = 0·0002) * P = 0.0013 ¥ p= 0.4289 36

The between group difference was −0·6% (p = 0·0262) VECTOR: HbA1c VECTOR - 2011 The between group difference was −0·6% (p = 0·0262) (7·7% to 7·2%) (7·2% vs 7·3%)

:Adherence VECTOR Only 1 patient in the Vildagliptin group missed at least one dose, compared with 10 patients in the SU group. p = 0·0204

* There are an estimated 325,000 Muslims with type 2 diabetes in the UK ** Hypoglycemic event (defined as blood glucose < 3.5 mmol ⁄ l with or without symptoms)

References: 1. Devendra D et al. Vildagliptin therapy and hypoglycaemia in Muslim type 2 diabetes patients during Ramadan. Int J Clin Pract, October 2009, 63, 10, 1446–1450.

How to Help Patients Fast Safely Patient Education Program. Select more safe drugs. Adjust dose if needed Ensure good non – sugar fluid intake. Avoid heavy physical exercise at afternoon. Ensure good calorie distribution.

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